Subchronic effects of clozapine and haloperidol on rats' forelimb force and duration during a press-while-licking task

Abstract

In order to compare and contrast the behavioral effects of the typical neuroleptic haloperidol with the atypical neuroleptic clozapine, ten daily doses of these drugs were administered to separate groups of rats trained to extend the forelimb through a rectangular hole and to exert downward pressure on a force transducer to gain access to water. Doses were individually titrated daily for each rat in an attempt to achieve a 50% reduction in time on task (analogous to response rate) during 8-min daily sessions. Clozapine-treated rats exhibited dramatic tolerance to the drug's suppressive effect on time on task. In contrast, haloperidol rats displayed little tolerance on this measure. Despite the tolerance reflected by time on task, no tolerance was seen in clozapine's marked slowing of the dominant frequency of oscillations in forelimb force as measured by Fourier analysis of the force-time recordings. Haloperidol did not slow the dominant frequency. No tolerance was seen for clozapine's effects on forelimb force or tremor measures. Haloperidol did not significantly affect forelimb force. Both haloperidol and clozapine produced increases in the duration of long-duration forelimb responses, and no tolerance was seen for either drug on this measure of behavior. For clozapine, the dissociation between the tendency to respond (time on task) and the observed slowing of the dominant frequency may reflect effects peculiar to atypical neuroleptics, while the lengthening of long-duration responses by both drugs may reflect a more general behavioral effect that is characteristic of both typical and atypical antipsychotic drugs.

Similarities and differences between the subchronic and withdrawal effects of clozapine and olanzapine on forelimb force steadiness

“…The effects observed here for subchronic clozapine (i.e., a decrease in time on task that diminished with repeated dosing, increased duration of long-duration responses, decreased frequency of the force oscillation related to the lick rhythm, decreased hold force, and decreased tremor power) were generally in agreement with previous studies using these methods Stanford and Fowler 1997). The only exception is that maximum force of the forelimb striking the operandum was diminished by clozapine in the current experiment, but this force-lowering effect, although in the same direction, was not strong enough to be statistically significant in the previous experiments with the same methods Stanford and Fowler 1997).…”

“…The only exception is that maximum force of the forelimb striking the operandum was diminished by clozapine in the current experiment, but this force-lowering effect, although in the same direction, was not strong enough to be statistically significant in the previous experiments with the same methods Stanford and Fowler 1997). A much earlier experiment based on brief ballistic forelimb responses found a force-lowering effect of clozapine (Ford et al 1979).…”

“…However, olanzapine did not significantly affect the force measures presumed to reflect reduced tremor (power in the 10-to 25-Hz band) or hypotonia (maximum force and hold force). In addition, olanzapine's suppression of behavioral output as measured by time on task remained robust, whereas clozapine's effect showed tolerance on this measure as expected (Stille et al 1971;Faustman and Fowler 1982;Sanger 1985;Kaempf and Porter 1987;Stanford and Fowler 1997).…”

“…The overarching purpose of the present work was to compare the behavioral effects of the atypical antipsychotics, clozapine (Coward 1993) and olanzapine (Moore et al 1992), in a task previously shown to detect both similarities and differences between the typical neuroleptic haloperidol and the atypical neuroleptic, clozapine (e.g., Fowler et al 1994;Stanford and Fowler 1997). In the two cited studies, haloperidol was observed to increase forelimb response force, increase forelimb tremor, and have little effect on the rats' lick rhythm frequency, whereas clozapine significantly decreased these behavioral measures.…”

“…Both haloperidol and clozapine increased the duration of long duration responses and reduced time on task, a measure of task engagement analogous to response rate. A second purpose of the experiment was to carry out the comparison with a 21-day subchronic dosing paradigm to determine whether or not olanzapine treatment manifests pronounced tolerance effects on some behavioral measures as clozapine does (Wiley et al 1994;Stanford and Fowler 1997). A third purpose of the work was to assess the effect of an anticholinergic probe (trihexyphenidyl) and a serotonergic agonist probe (quipazine) in clozapine-or olanzapinetreated rats as a comparison technique, since both clozapine and olanzapine have substantial antimuscarinic and antiserotonergic (5HT 2a ) activity (Moore et al 1993).…”